CN112409286A - Synthesis method of N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone - Google Patents
Synthesis method of N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone Download PDFInfo
- Publication number
- CN112409286A CN112409286A CN202010062277.2A CN202010062277A CN112409286A CN 112409286 A CN112409286 A CN 112409286A CN 202010062277 A CN202010062277 A CN 202010062277A CN 112409286 A CN112409286 A CN 112409286A
- Authority
- CN
- China
- Prior art keywords
- hydroxymethyl
- substituted phenyl
- oxazolidinone
- phenyl
- epichlorohydrin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a synthetic method of N-substituted phenyl-5-hydroxymethyl-2-oxazolidone, which is characterized by comprising the following steps: with 3-R2‑4‑R1-aniline and epichlorohydrin are used as raw materials to react, and the product obtained by the reaction is under alkaline condition and CO2Preparing N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone under an atmosphere, wherein R1Is a morpholine group, a morpholine-3-one group or a piperazine group and derivatives thereof, R2Is halogen, hydrogen or lower alkyl. The synthesis method provided by the invention has the advantages of few steps, simple operation, cheap and easily-obtained raw materials, mild reaction conditions, high product yield and the like, and is particularly suitable for industrial production of an antibiotic linezolid intermediate and an antithrombotic drug rivaroxaban intermediate.
Description
Technical Field
The invention belongs to the field of synthesis of drug intermediates, and particularly relates to a synthesis method of N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone.
Background
(R) -N-substituted phenyl-5-hydroxymethyl-2-oxazolidinones
Is an intermediate of antibiotic Linezolid
And an intermediate of the antithrombotic Rivaroxaban (Rivaroxaban)
The main structure of (1). Taking linezolid intermediate as an example, the following synthesis methods are mainly adopted:
patent document WO9507271 reports the following synthetic method:
the patent reports that 3-fluoro-4-morpholine aniline reacts with benzyl chloroformate, then the reaction product reacts with (R) -glycidic butyrate under the protection of nitrogen and the action of strong base n-butyl lithium at the temperature of-78 ℃ to obtain a target product. The method uses high-risk and flammable n-butyllithium, requires the system to be anhydrous and anaerobic, has the reaction temperature of-78 ℃, has large operation difficulty and danger, and is not suitable for large-scale industrialization.
Patent document WO2012114355 reports the following synthesis method:
the patent reports that 3-fluoro-4-morpholinylaniline reacts with (R) -epichlorohydrin, then CDI (N, N' -carbonyldiimidazole) is used for cyclization to generate (5R) -3- [ 3-fluoro-4- (4-morpholinyl) phenyl ] -5-chloromethyl-2-oxazolidone, and the reaction is carried out with sodium acetate in DMF solvent at 120 ℃ and then the hydrolysis is carried out to prepare the linezolid intermediate. The process route has the advantages of low yield, more impurities, more process steps and higher cost.
The patent document with publication number CN1772750 reports the following synthesis method:
the patent reports that 3-fluoro-4-morpholinylaniline reacts with triphosgene to generate 3-fluoro-4-morpholinylphenylisonitrile acid ester, and the 3-fluoro-4-morpholinylphenylisonitrile ester reacts with (R) -glycidic butyrate to obtain the target product, but anhydrous lithium bromide and tributyl phosphorus oxide used in the method are not easily obtained.
The patent document with publication number WO2014045292A reports the following synthetic method:
the method comprises the following steps:
the second method comprises the following steps:
the patent route uses 3-fluoro-4-morpholine aniline to react with (R) -glycidol, then uses CDI or BOC anhydride to react, and uses sodium methoxide to cyclize to obtain the target product, and the route has the defects that the (R) -glycidol is expensive, is easy to self-polymerization and generate heat, and has potential explosion hazard; 3-fluoro-4-morpholine aniline and (R) -glycidyl butyrate are used as raw materials to react, the reaction is incomplete, and impurity dimers are generated.
Organic Letters 201820 (16),5036 and 5039 report the use of CO2The method for synthesizing the (R) -N-substituted phenyl-5-hydroxymethyl-2-oxazolidone by two steps under the action of the aluminum catalyst comprises the following steps:
the method has simple steps, but racemization is easy to occur in the (S) -1-chloro-3- (substituted phenylamino) -2-propanol epoxy process, the proportion of chiral products is reduced, an aluminum catalyst is used in the reaction process, and the catalyst is expensive in preparation raw materials and complex in process, so that the method is not suitable for industrial production.
Journal of Organic Chemistry,70(14),5737-5740 reports the following synthetic methods:
the method uses the reaction of benzylamine and (S) -epichlorohydrin to prepare (R) -N-substituted benzyl-5-hydroxymethyl-2-oxazolidone. The carbonate used in the reaction is sodium carbonate, potassium carbonate, rubidium carbonate and the like, the conversion rate of more than 75 percent can be achieved only by greatly excessive carbonate and triethylamine in the reaction process, and the production cost of the method is high. However, this document does not report the use of this method for the preparation of linezolid intermediate (5R) -3- [ 3-fluoro-4- (4-morpholinyl) phenyl ] -5-hydroxymethyl-2-oxazolidinone and rivaroxaban intermediate (R) -4- [4- (5-hydroxymethyl-2-oxo-oxazolin-3-yl) -phenyl ] -morpholin-3-one. And when the method is used for preparing the two intermediates, the yield is extremely low.
None of the previously disclosed processes for the preparation of N-substituted phenyl-5-hydroxymethyl-2-oxazolidinones is satisfactory for industrial production.
Disclosure of Invention
The invention aims to provide a synthetic method of N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone, which has the advantages of simplicity, greenness and higher yield.
The technical scheme adopted by the invention is as follows:
a synthetic method of N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone comprises the following steps: with 3-R2-4-R1-aniline and epichlorohydrin are used as raw materials to react, and the product obtained by the reaction is under alkaline condition and CO2Preparing N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone under an atmosphere, wherein R1Is a morpholine group, a morpholine-3-one group or a piperazine group and derivatives thereof, R2Is halogen, hydrogen or lower alkyl.
The synthesis method is a one-pot method, and comprises the following steps: with 3-R2-4-R1Preparing 1-chloro-3- (3-R) by using (E) -aniline and epoxy chloropropane as raw materials2-4-R1-phenylamino) -2-propanol, wherein R is1Is a morpholine group, a morpholine-3-one group or a piperazine group and derivatives thereof, R2Is halogen, hydrogen or lower alkyl; adding inorganic base or organic base and introducing CO21-chloro-3- (3-R)2-4-R1-phenylamino) -2-propanol with CO2Carrying out cyclization reaction to obtain the N-substituted phenyl-5-hydroxymethyl-2-oxazolidone.
Specifically, the reaction route of the synthetic method is shown as follows, wherein the formula (II) is 3-R2-4-R1-aniline, epichlorohydrin in formula (III) and 1-chloro-3- (3-R) in formula (IV)2-4-R1-phenylamino) -2-propanol, N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone of formula (i):
in the invention, (R) -N-substituted phenyl-5-hydroxymethyl-2-oxazolidone is obtained by using (S) -epichlorohydrin as a reaction raw material, and (S) -N-substituted phenyl-5-hydroxymethyl-2-oxazolidone is obtained by using (R) -epichlorohydrin as a reaction raw material; using racemic epichlorohydrin as a reaction raw material to obtain racemic N-substituted phenyl-5-hydroxymethyl-2-oxazolidone.
Preferably, the 1-chloro-3- (3-R)2-4-R1The preparation method of the (E) -phenylamino) -2-propanol comprises the following steps: reacting 3-R2-4-R1Dissolving aniline, epoxy chloropropane and boron trifluoride diethyl etherate in an organic solvent, and reacting at 30-70 ℃ for 12-24 h.
Preferably, in 1-chloro-3- (3-R)2-4-R1-phenylamino) -2-propanol, the 3-R2-4-R1The proportion of the aniline, the epichlorohydrin and the boron trifluoride diethyl etherate is 0.8-5: 1: 0.05-0.2.
Preferably, the temperature of the cyclization reaction is 20-100 ℃.
Preferably, said 3-R2-4-R1The molar ratio of the aniline to the inorganic base or the organic base is 1: 1-20.
The organic base is selected from one or a combination of at least two of organic amine, sodium methoxide or sodium ethoxide.
The organic amine is selected from one or the combination of at least two of triethylamine, tetramethylguanidine, 1, 8-diazabicycloundec-7-ene, pyridine, piperidine, quinoline, 4-dimethylamino pyridine or N-methylmorpholine.
The inorganic base is selected from one or a combination of at least two of sodium carbonate, potassium carbonate, trisodium phosphate or tripotassium phosphate.
Preferably, the synthesis method comprises the following steps: with 3-R2-4-R1Preparing (5R) -3- [ 3-fluoro-4- (4-morpholinyl) phenyl group by taking 3-fluoro-4-morpholinylaniline or 4- (4-aminophenyl) -morpholin-3-one and (S) -epichlorohydrin as raw materials]-5-hydroxymethyl-2-oxazolidinone or (R) -4- [4- (5-hydroxymethyl-2-oxooxazolidin-3-yl) -phenyl]-morpholin-3-one.
Further preferred, said (R) -4- [4- (5-hydroxymethyl-2-oxooxazolidin-3-yl) -phenyl]The synthesis method of the (E) -morpholine-3-ketone comprises the following steps: dissolving 4- (4-aminophenyl) -morpholin-3-one, (S) -epichlorohydrin and boron trifluoride diethyl etherate in a molar ratio of 1:1: 0.06-0.2 in an organic solvent, and reacting at 70 ℃ to prepare (S) -4- (- ((3-chloro-2-hydroxypropyl) amino) phenyl) morpholin-3-one; adding pyridine or piperidine and introducing CO2Performing cyclization reaction at 30-50 deg.C to obtain (R) -4- [4- (5-hydroxymethyl-2-oxo-oxazolidin-3-yl) -phenyl]-morpholin-3-one.
In the synthetic method provided by the inventionCO2Plays a key role in the cyclization process, and compared with the method reported by Organic Letters 201820 (16),5036-5039, the method avoids the cyclization process of racemizing the product, does not need to use a catalyst, improves the yield of the chiral product of the reaction and reduces the production cost. The invention has the beneficial effect that 3-R is used2-4-R1-aniline and epichlorohydrin as raw materials in CO2The N-substituted phenyl-5-hydroxymethyl-2-oxazolidone can be prepared by a one-pot method under the atmosphere. The method has the advantages of few steps, simple operation, cheap and easily obtained raw materials, mild reaction conditions, high product yield and the like, and is particularly suitable for industrial production of the antibiotic linezolid intermediate and the antithrombotic drug rivaroxaban intermediate.
Drawings
FIG. 1 shows NMR spectra of (5R) -3- [ 3-fluoro-4- (4-morpholinyl) phenyl ] -5-hydroxymethyl-2-oxazolidinone prepared in the examples;
FIG. 2 is a nuclear magnetic resonance spectrum of (R) -4- [4- (5-hydroxymethyl-2-oxooxazolidin-3-yl) -phenyl ] -morpholin-3-one prepared in example.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be further described in detail with reference to the accompanying drawings and examples. It should be understood that the detailed description and specific examples, while indicating the scope of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.
EXAMPLE 1 preparation of (5R) -3- [ 3-fluoro-4- (4-morpholinyl) phenyl ] -5-hydroxymethyl-2-oxazolidinone
Dissolving 20.0g of 3-fluoro-4-morpholinylaniline, 9.5g of (S) -epichlorohydrin and 0.9g of boron trifluoride diethyl etherate in 200.0g N, N-dimethylformamide, and reacting at 50 ℃ for 16h to prepare (S) -1-chloro-3- ((3-fluoro-4-morpholinophenyl) amino) -2-propanol; adding 32.1g of triethylamine into the system, heating to 90 ℃, and introducing CO into the solution2After the reaction is finished, filtering, concentrating under reduced pressure, adding 100ml of water and 200ml of dichloromethane, demixing, concentrating the organic layer under reduced pressure, adding 100g of ethyl acetate, heating to 85 ℃, slowly cooling to 5 ℃, crystallizing, filtering and drying to obtain 22.6g of (5R) -3- [ 3-fluoro-4- (4-morpholine)Linyl) phenyl]-5-hydroxymethyl-2-oxazolidinone in a yield of 74.8% with ee > 99% by HPLC chiral analysis.
This example prepared (5R) -3- [ 3-fluoro-4- (4-morpholinyl) phenyl]Nuclear magnetic resonance data for 5-hydroxymethyl-2-oxazolidinone are:1H NMR(500MHz,Chloroform-d)δ7.43(dd,1H),7.09(dd,1H),6.90(t,1H),4.72(ddt,1H),4.02–3.90(m,3H),3.89–3.83(m,4H),3.72(q,2H),3.03(dd,4H)；13C NMR(126MHz,CDCl3)δ156.35,154.95,154.39,136.21,133.27,133.19,118.82,118.79,113.91,113.88,107.49,107.28,77.35,77.30,77.10,76.85,73.12,66.90,62.49,62.44,50.98,50.96,46.37。
EXAMPLE 2 preparation of (5R) -3- [ 3-fluoro-4- (4-morpholinyl) phenyl ] -5-hydroxymethyl-2-oxazolidinone
(S) -1-chloro-3- ((3-fluoro-4-morpholinophenyl) amino) -2-propanol was prepared by dissolving 20.0g of 3-fluoro-4-morpholinoaniline, 9.5g of (S) -epichlorohydrin and 1.2g of boron trifluoride in 200.0g N, N-dimethylformamide and reacting at 40 ℃ for 24 hours; then 20.0g of 28% sodium methoxide methanol solution is added into the system, the temperature is raised to 95 ℃, CO is introduced into the solution2After the reaction, the mixture was filtered, concentrated under reduced pressure, added with 100ml of water and 200ml of dichloromethane, layered, the organic layer was concentrated under reduced pressure, added with 100g of ethyl acetate, heated to 85 ℃, slowly cooled to 5 ℃, crystallized, filtered and dried to obtain 21.8g of (5R) -3- [ 3-fluoro-4- (4-morpholinyl) phenyl]-5-hydroxymethyl-2-oxazolidinone in a yield of 72.2% with ee > 99% by HPLC chiral analysis.
EXAMPLE 3 preparation of (5R) -3- [ 3-fluoro-4- (4-morpholinyl) phenyl ] -5-hydroxymethyl-2-oxazolidinone
(S) -1-chloro-3- ((3-fluoro-4-morpholinophenyl) amino) -2-propanol was prepared by dissolving 20.0g of 3-fluoro-4-morpholinoaniline, 9.5g of (S) -epichlorohydrin and 0.4g of boron trifluoride in 200.0g N, N-dimethylformamide and reacting at 60 ℃ for 12 hours; adding 33.5g of trisodium phosphate into the system, heating to 90 ℃, and introducing CO into the solution2After the reaction, the mixture was filtered, concentrated under reduced pressure, added with 100ml of water and 200ml of dichloromethane, layered, the organic layer was concentrated under reduced pressure, added with 100g of ethyl acetate, heated to 85 ℃, slowly cooled to 5 ℃, crystallized, filtered and dried to obtain 22.3g of (5R) -3- [ 3-fluoro-4- (4-morpholinyl) 4) Phenyl radical]-5-hydroxymethyl-2-oxazolidinone in 73.8% yield with ee > 99% by HPLC chiral analysis.
EXAMPLE 4 preparation of (5R) -3- [ 3-fluoro-4- (4-morpholinyl) phenyl ] -5-hydroxymethyl-2-oxazolidinone
Dissolving 20.0g of 3-fluoro-4-morpholinylaniline, 9.5g of (S) -epichlorohydrin and 0.9g of boron trifluoride diethyl etherate in 200.0g N, N-dimethylformamide, and reacting at 60 ℃ for 16h to prepare (S) -1-chloro-3- ((3-fluoro-4-morpholinophenyl) amino) -2-propanol; then 12.9g of tetramethylguanidine is added into the system, the temperature is raised to 55 ℃, CO is introduced into the solution2After the reaction, the mixture was concentrated under reduced pressure, 100ml of water and 200ml of dichloromethane were added, the layers were separated, and the organic layer was concentrated under reduced pressure, 100g of ethyl acetate was added, the temperature was raised to 85 ℃, the temperature was slowly lowered to 5 ℃, the crystals were filtered and dried to obtain 22.7g of (5R) -3- [ 3-fluoro-4- (4-morpholinyl) phenyl]-5-hydroxymethyl-2-oxazolidinone in a yield of 75.2% with ee > 99% by HPLC chiral analysis.
EXAMPLE 5 preparation of (5R) -3- [ 3-fluoro-4- (4-morpholinyl) phenyl ] -5-hydroxymethyl-2-oxazolidinone
Dissolving 20.0g of 3-fluoro-4-morpholinylaniline, 9.5g of (S) -epichlorohydrin and 0.9g of boron trifluoride diethyl etherate in 200.0g N, N-dimethylformamide, and reacting at 60 ℃ for 16h to prepare (S) -1-chloro-3- ((3-fluoro-4-morpholinophenyl) amino) -2-propanol; adding 17.0g DBU into the system, heating to 55 ℃, and introducing CO into the solution2After the reaction, the mixture was concentrated under reduced pressure, 100ml of water and 200ml of dichloromethane were added, the layers were separated, and the organic layer was concentrated under reduced pressure, 100g of ethyl acetate was added, the temperature was raised to 85 ℃, the temperature was slowly lowered to 5 ℃, the crystals were filtered and dried to obtain 22.3g of (5R) -3- [ 3-fluoro-4- (4-morpholinyl) phenyl]-5-hydroxymethyl-2-oxazolidinone in 73.8% yield with ee > 99% by HPLC chiral analysis.
EXAMPLE 6 preparation of (5R) -3- [ 3-fluoro-4- (4-morpholinyl) phenyl ] -5-hydroxymethyl-2-oxazolidinone
(S) -1-chloro-3- ((3-fluoro-4-morpholinophenyl) amino) -2-propanol was prepared by dissolving 20.0g of 3-fluoro-4-morpholinoaniline, 9.5g of (S) -epichlorohydrin and 0.9g of boron trifluoride in 200.0g N, N-dimethylformamide and reacting at 50 ℃ for 18 hours; then 15.4g quinoline is added into the system, the temperature is raised to 70 ℃, CO is pumped into the solution2After the reaction, the mixture was concentrated under reduced pressure, 100ml of water and 200ml of dichloromethane were added, the layers were separated, and the organic layer was concentrated under reduced pressure, 100g of ethyl acetate was added, the temperature was raised to 85 ℃, the temperature was slowly lowered to 5 ℃, the crystals were filtered and dried to obtain 22.1g of (5R) -3- [ 3-fluoro-4- (4-morpholinyl) phenyl]-5-hydroxymethyl-2-oxazolidinone in a yield of 72.9% with ee > 99% by HPLC chiral analysis.
EXAMPLE 7 preparation of (R) -4- [4- (5-hydroxymethyl-2-oxooxazolidin-3-yl) -phenyl ] -morpholin-3-one
(S) -4- (4- ((3-chloro-2-hydroxypropyl) amino) phenyl) morpholin-3-one is prepared by dissolving 20.0g of 4- (4-aminophenyl) -morpholin-3-one, 9.7g of (S) -epichlorohydrin and 0.9g of boron trifluoride diethyl etherate in 200.0g N, N-dimethylformamide and reacting at 60 ℃ for 14 h; adding 45g of potassium carbonate into the system, heating to 90 ℃, and introducing CO into the solution2After the reaction is finished, filtering, concentrating under reduced pressure, adding 100ml of water and 200ml of dichloromethane, demixing, concentrating the organic layer under reduced pressure, adding 100g of ethyl acetate, heating to 80 ℃, slowly cooling to 5 ℃, crystallizing, filtering and drying to obtain 21.8g of (R) -4- [4- (5-hydroxymethyl-2-oxo-oxazolidin-3-yl) -phenyl]-morpholin-3-one in 71.7% yield with chiral HPLC analysis ee > 99%.
(R) -4- [4- (5-hydroxymethyl-2-oxo-oxazolin-3-yl) -phenyl prepared in this example]Nuclear magnetic resonance data for-morpholin-3-one are:1H NMR(500MHz,DMSO-d6)δ7.63–7.56(m,2H),7.44–7.37(m,2H),5.23(t,1H),4.70(ddt,1H),4.20(s,2H),4.09(t,1H),4.00–3.94(m,2H),3.84(dd,1H),3.68(td,2H),3.57(ddd,1H)；13C NMR(126MHz,DMSO)δ165.94,154.45,136.80,136.66,125.92,117.99,73.14,67.69,63.45,61.62,48.99,46.00,40.05,39.96,39.88,39.79,39.71,39.62,39.55,39.46,39.38,39.29,39.12,38.96。
EXAMPLE 8 preparation of (R) -4- [4- (5-hydroxymethyl-2-oxo-oxazolin-3-yl) -phenyl ] -morpholin-3-one
(S) -4- (4- ((3-chloro-2-hydroxypropyl) amino) phenyl) morpholin-3-one is prepared by dissolving 20.0g of 4- (4-aminophenyl) -morpholin-3-one, 9.7g of (S) -epichlorohydrin and 0.9g of boron trifluoride diethyl etherate in 200.0g N, N-dimethylformamide and reacting at 50 ℃ for 16 h; 13.1g of tetramethylguanidine was added to the system, and the temperature was raised to 20Introducing CO into the solution at the temperature of2After the reaction is finished, concentrating under reduced pressure, adding 100ml of water and 200ml of dichloromethane, demixing, concentrating the organic layer under reduced pressure, adding 100g of ethyl acetate, heating to 80 ℃, slowly cooling to 5 ℃, crystallizing, filtering and drying to obtain 22.3g of (R) -4- [4- (5-hydroxymethyl-2-oxo-oxazolidin-3-yl) -phenyl]-morpholin-3-one in 73.3% yield with ee > 99% by HPLC chiral analysis.
EXAMPLE 9 preparation of (R) -4- [4- (5-hydroxymethyl-2-oxo-oxazolin-3-yl) -phenyl ] -morpholin-3-one
(S) -4- (4- ((3-chloro-2-hydroxypropyl) amino) phenyl) morpholin-3-one is prepared by dissolving 20.0g of 4- (4-aminophenyl) -morpholin-3-one, 9.7g of (S) -epichlorohydrin and 0.9g of boron trifluoride diethyl etherate in 200.0g N, N-dimethylformamide and reacting at 70 ℃ for 13 h; adding 27.1g pyridine into the system, heating to 30 ℃, and introducing CO into the solution2After the reaction is finished, concentrating under reduced pressure, adding 100ml of water and 200ml of dichloromethane, demixing, concentrating the organic layer under reduced pressure, adding 100g of ethyl acetate, heating to 80 ℃, slowly cooling to 5 ℃, crystallizing, filtering and drying to obtain 25.3g of (R) -4- [4- (5-hydroxymethyl-2-oxo-oxazolidin-3-yl) -phenyl]-morpholin-3-one in 83.2% yield with ee > 99% by HPLC chiral analysis.
EXAMPLE 10 preparation of (R) -4- [4- (5-hydroxymethyl-2-oxo-oxazolin-3-yl) -phenyl ] -morpholin-3-one
(S) -4- (4- ((3-chloro-2-hydroxypropyl) amino) phenyl) morpholin-3-one is prepared by dissolving 20.0g of 4- (4-aminophenyl) -morpholin-3-one, 9.3g of (S) -epichlorohydrin and 2.8g of boron trifluoride diethyl etherate in 200.0g N, N-dimethylformamide and reacting at 70 ℃ for 13 h; adding 43.0g piperidine into the system, heating to 50 ℃, and introducing CO into the solution2After the reaction is finished, concentrating under reduced pressure, adding 100ml of water and 200ml of dichloromethane, demixing, concentrating the organic layer under reduced pressure, adding 100g of ethyl acetate, heating to 80 ℃, slowly cooling to 5 ℃, crystallizing, filtering and drying to obtain 26.9g of (R) -4- [4- (5-hydroxymethyl-2-oxo-oxazolidin-3-yl) -phenyl]-morpholin-3-one in 88.4% yield with chiral HPLC analysis ee > 99%.
EXAMPLE 11 preparation of (R) -4- [4- (5-hydroxymethyl-2-oxo-oxazolin-3-yl) -phenyl ] -morpholin-3-one
(S) -4- (4- ((3-chloro-2-hydroxypropyl) amino) phenyl) morpholin-3-one is prepared by dissolving 20.0g of 4- (4-aminophenyl) -morpholin-3-one, 9.7g of (S) -epichlorohydrin and 0.9g of boron trifluoride diethyl etherate in 200.0g N, N-dimethylformamide and reacting at 60 ℃ for 14 h; adding 17.3g DMAP into the system, heating to 30 ℃, and introducing CO into the solution2After the reaction is finished, concentrating under reduced pressure, adding 100ml of water and 200ml of dichloromethane, demixing, concentrating the organic layer under reduced pressure, adding 100g of ethyl acetate, heating to 80 ℃, slowly cooling to 5 ℃, crystallizing, filtering and drying to obtain 20.9g of (R) -4- [4- (5-hydroxymethyl-2-oxo-oxazolidin-3-yl) -phenyl]-morpholin-3-one in 68.9% yield with ee > 99% by HPLC chiral analysis.
EXAMPLE 12(R) -4- [4- (5-hydroxymethyl-2-oxo-oxazolin-3-yl) -phenyl]Preparation of-morpholin-3-one (S) -4- (4- ((3-chloro-2-hydroxypropyl) amino) phenyl) morpholin-3-one is prepared by dissolving 20.0g of 4- (4-aminophenyl) -morpholin-3-one, 9.7g of (S) -epichlorohydrin and 0.9g of boron trifluoride diethyl etherate in 200.0g N, and reacting for 24h at 30 ℃; adding 26.8g N-methylmorpholine into the system, heating to 50 ℃, and introducing CO into the solution2After the reaction is finished, concentrating under reduced pressure, adding 100ml of water and 200ml of dichloromethane, demixing, concentrating the organic layer under reduced pressure, adding 100g of ethyl acetate, heating to 80 ℃, slowly cooling to 5 ℃, crystallizing, filtering and drying to obtain 21.9g of (R) -4- [4- (5-hydroxymethyl-2-oxo-oxazolidin-3-yl) -phenyl]-morpholin-3-one in 72.2% yield with ee > 99% by HPLC chiral analysis.
Wherein, the nuclear magnetic resonance spectrum of (5R) -3- [ 3-fluoro-4- (4-morpholinyl) phenyl ] -5-hydroxymethyl-2-oxazolidinone prepared in examples 1 to 6 is shown in figure 1. The NMR spectra of (R) -4- [4- (5-hydroxymethyl-2-oxooxazolidin-3-yl) -phenyl ] -morpholin-3-one prepared in examples 7-12 are shown in FIG. 2.
The above-mentioned embodiments are intended to illustrate the technical solutions and advantages of the present invention, and it should be understood that the above-mentioned embodiments are only the most preferred embodiments of the present invention, and are not intended to limit the present invention, and any modifications, additions, equivalents, etc. made within the scope of the principles of the present invention should be included in the scope of the present invention.
Claims (11)
1. A synthetic method of N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone is characterized by comprising the following steps: with 3-R2-4-R1-aniline and epichlorohydrin are used as raw materials to react, and the product obtained by the reaction is under alkaline condition and CO2Preparing N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone under an atmosphere, wherein R1Is a morpholine group, a morpholine-3-one group or a piperazine group and derivatives thereof, R2Is halogen, hydrogen or lower alkyl.
2. The synthesis method of N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone according to claim 1, wherein the synthesis method is a one-pot method, and the synthesis method comprises the following steps: with 3-R2-4-R1Preparing 1-chloro-3- (3-R) by using (E) -aniline and epoxy chloropropane as raw materials2-4-R1-phenylamino) -2-propanol, wherein R is1Is a morpholine group, a morpholine-3-one group or a piperazine group and derivatives thereof, R2Is halogen, hydrogen or lower alkyl; adding inorganic base or organic base and introducing CO21-chloro-3- (3-R)2-4-R1-phenylamino) -2-propanol with CO2Carrying out cyclization reaction to obtain the N-substituted phenyl-5-hydroxymethyl-2-oxazolidone.
3. The method for synthesizing N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone according to claim 1 or 2, wherein (R) -N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone is obtained using (S) -epichlorohydrin as a reaction raw material; using (R) -epoxy chloropropane as a reaction raw material to obtain (S) -N-substituted phenyl-5-hydroxymethyl-2-oxazolidone; using racemic epichlorohydrin as a reaction raw material to obtain racemic N-substituted phenyl-5-hydroxymethyl-2-oxazolidone.
4. A process for the synthesis of N-substituted phenyl-5-hydroxymethyl-2-oxazolidinones as claimed in claim 2 where the 1-chloro-3- (3-R) is2-4-R1Preparation of (E) -phenylamino) -2-propanolThe preparation method comprises the following steps: reacting 3-R2-4-R1Dissolving aniline, epoxy chloropropane and boron trifluoride diethyl etherate in an organic solvent, and reacting at 30-70 ℃ for 12-24 h.
5. A process for the synthesis of N-substituted phenyl-5-hydroxymethyl-2-oxazolidinones as claimed in claim 4 where the 3-R is2-4-R1The mol ratio of the aniline to the epichlorohydrin to the boron trifluoride diethyl etherate is 0.8-5: 1: 0.05-0.2.
6. The method for synthesizing N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone according to claim 2, wherein the temperature of the cyclization reaction is 20-100 ℃.
7. A process for the synthesis of N-substituted phenyl-5-hydroxymethyl-2-oxazolidinones as claimed in claim 2 where the 3-R is2-4-R1The molar ratio of the aniline to the inorganic base or the organic base is 1: 1-20.
8. The method for synthesizing N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone according to claim 7, wherein the organic base is selected from one or a combination of at least two of organic amine, sodium methoxide or sodium ethoxide.
9. A process for the synthesis of an N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone as claimed in claim 8 where the organic amine is selected from one or a combination of at least two of triethylamine, tetramethylguanidine, 1, 8-diazabicycloundec-7-ene, pyridine, piperidine, quinoline, 4-dimethylaminopyridine or N-methylmorpholine.
10. A process for the synthesis of N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone as claimed in claim 7 where the inorganic base is selected from one or a combination of at least two of sodium carbonate, potassium carbonate, trisodium phosphate or tripotassium phosphate.
11. A method of synthesizing an N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone as defined in claim 1, wherein the method comprises: with 3-R2-4-R1Preparing (5R) -3- [ 3-fluoro-4- (4-morpholinyl) phenyl group by taking 3-fluoro-4-morpholinylaniline or 4- (4-aminophenyl) -morpholin-3-one and (S) -epichlorohydrin as raw materials]-5-hydroxymethyl-2-oxazolidinone or (R) -4- [4- (5-hydroxymethyl-2-oxooxazolidin-3-yl) -phenyl]-morpholin-3-one.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910771167 | 2019-08-20 | ||
| CN2019107711670 | 2019-08-20 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112409286A true CN112409286A (en) | 2021-02-26 |
| CN112409286B CN112409286B (en) | 2022-08-05 |
Family
ID=74660096
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010062277.2A Active CN112409286B (en) | 2019-08-20 | 2020-01-19 | Synthesis method of N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US20220267284A1 (en) |
| EP (1) | EP4001268A4 (en) |
| CN (1) | CN112409286B (en) |
| CA (1) | CA3148367C (en) |
| IL (1) | IL290582A (en) |
| WO (1) | WO2021031533A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117586197A (en) * | 2023-06-25 | 2024-02-23 | 南京先进生物材料与过程装备研究院有限公司 | Method for preparing oxazolidinone and derivatives thereof by catalyzing carbon dioxide and epoxy amine under normal pressure |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001213868A (en) * | 2000-01-27 | 2001-08-07 | Natl Inst Of Advanced Industrial Science & Technology Meti | Method for producing oxazolidone |
| CN1369489A (en) * | 2002-01-25 | 2002-09-18 | 中国科学院上海有机化学研究所 | Process for reaction of CO2 on heterocyclic compound under co-catalysis of transistion metal complex and organic alkali |
| US20050154200A1 (en) * | 2004-01-13 | 2005-07-14 | Mitsubishi Gas Chemical Company, Inc. | Method for producing cyclic carbamate ester |
| CN101817764A (en) * | 2010-05-26 | 2010-09-01 | 中国科学院长春应用化学研究所 | Preparation method of chain-like urea derivatives, cyclic urea derivatives and oxazolidinone |
| CN102000487A (en) * | 2010-10-19 | 2011-04-06 | 上海海事大学 | Method for capturing carbon dioxide |
| CN102311402A (en) * | 2011-07-18 | 2012-01-11 | 苏州敬业医药化工有限公司 | Preparation method of 3-substituted phenyl-5-hydroxymethyl oxazolidine-2-ketone |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MY115155A (en) | 1993-09-09 | 2003-04-30 | Upjohn Co | Substituted oxazine and thiazine oxazolidinone antimicrobials. |
| CN1772750A (en) | 2005-11-15 | 2006-05-17 | 郑州大学 | Prepn process of (R)-N-(3-fluoro-4-morpholinyl phenyl)-oxazolone-5-methyl alcohol |
| SI2595968T1 (en) * | 2011-02-24 | 2016-01-29 | Lee Pharma Limited | Novel process for preparation of linezolid and its novel intermediates |
| CN103570640A (en) * | 2012-07-30 | 2014-02-12 | 华东师范大学 | Carbon dioxide one-pot method for directly preparing oxazolidine-2-one compounds |
| WO2014045292A1 (en) | 2012-09-20 | 2014-03-27 | Symed Labs Limited | Improved process for the preparation of linezolid intermediate |
| CN105153059B (en) * | 2015-09-11 | 2018-03-06 | 苏州大学 | The preparation method of Yi Zhong oxazolidinone compounds |
-
2020
- 2020-01-19 CN CN202010062277.2A patent/CN112409286B/en active Active
- 2020-02-10 EP EP20855573.0A patent/EP4001268A4/en active Pending
- 2020-02-10 WO PCT/CN2020/074576 patent/WO2021031533A1/en unknown
- 2020-02-10 US US17/636,869 patent/US20220267284A1/en active Pending
- 2020-02-10 CA CA3148367A patent/CA3148367C/en active Active
-
2022
- 2022-02-13 IL IL290582A patent/IL290582A/en unknown
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001213868A (en) * | 2000-01-27 | 2001-08-07 | Natl Inst Of Advanced Industrial Science & Technology Meti | Method for producing oxazolidone |
| CN1369489A (en) * | 2002-01-25 | 2002-09-18 | 中国科学院上海有机化学研究所 | Process for reaction of CO2 on heterocyclic compound under co-catalysis of transistion metal complex and organic alkali |
| US20050154200A1 (en) * | 2004-01-13 | 2005-07-14 | Mitsubishi Gas Chemical Company, Inc. | Method for producing cyclic carbamate ester |
| CN101817764A (en) * | 2010-05-26 | 2010-09-01 | 中国科学院长春应用化学研究所 | Preparation method of chain-like urea derivatives, cyclic urea derivatives and oxazolidinone |
| CN102000487A (en) * | 2010-10-19 | 2011-04-06 | 上海海事大学 | Method for capturing carbon dioxide |
| CN102311402A (en) * | 2011-07-18 | 2012-01-11 | 苏州敬业医药化工有限公司 | Preparation method of 3-substituted phenyl-5-hydroxymethyl oxazolidine-2-ketone |
Non-Patent Citations (3)
| Title |
|---|
| JEROEN RINTJEMA，ET AL.: ""Substrate-Controlled Product Divergence: Conversion of CO2 into Heterocyclic Products"", 《ANGEW. CHEM. INT. ED.》 * |
| YASUNORI TODA，ET AL.: ""Switchable synthesis of cyclic carbamates by carbon dioxide fixation at atmospheric pressure"", 《CHEM. COMMUN.》 * |
| YUSEOP LEE，ET AL.: ""Stereocontrolled, Divergent, Al(lll)-Catalyzed Coupling of Chiral N‑Aryl Epoxy Amines and CO2"", 《ORG. LETT.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117586197A (en) * | 2023-06-25 | 2024-02-23 | 南京先进生物材料与过程装备研究院有限公司 | Method for preparing oxazolidinone and derivatives thereof by catalyzing carbon dioxide and epoxy amine under normal pressure |
Also Published As
| Publication number | Publication date |
|---|---|
| CA3148367C (en) | 2024-03-05 |
| EP4001268A1 (en) | 2022-05-25 |
| EP4001268A4 (en) | 2022-08-17 |
| US20220267284A1 (en) | 2022-08-25 |
| WO2021031533A1 (en) | 2021-02-25 |
| CN112409286B (en) | 2022-08-05 |
| IL290582A (en) | 2022-04-01 |
| CA3148367A1 (en) | 2021-02-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1768967A1 (en) | Novel intermediates for linezolid and related compounds | |
| CN114478690B (en) | Preparation method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane derivative | |
| CN112409286B (en) | Synthesis method of N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone | |
| WO2013105100A1 (en) | Processes for the preparation of 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene-carboxamide and intermediates thereof | |
| CN111587240B (en) | Intermediate of optically active piperidine derivative and process for producing the same | |
| CN112358419B (en) | Synthesis process of 3, 4-dichlorophenyl isocyanate | |
| CN111592467A (en) | Nilaparib intermediate, preparation method and application thereof, and synthesis method of nilapab | |
| EP2360160B1 (en) | Intermediates and their use for producing benzoxazine derivative | |
| RU2792687C1 (en) | Method for synthesis of n-substituted phenyl-5-hydroxymethyl-2-oxazolidinone | |
| US5618949A (en) | Process for synthesis of chiral cis- and trans-3-amino-4-substituted pyrrolidine compounds | |
| CN114163445B (en) | Larotinib intermediate and preparation method thereof | |
| CN107663170B (en) | Method for preparing besifloxacin intermediate compound | |
| CN111646991B (en) | Preparation method of avibactam sodium intermediate | |
| CN114014864A (en) | Preparation process of traasiril compound | |
| US9169221B2 (en) | Dihydro 1,4-benzoxazines and method of synthesizing the same using sulfonium salts | |
| CN104086475B (en) | A kind of preparation method of N-benzyloxycarbonyl group-L-prolineamide | |
| CN103833717B (en) | A kind of synthetic method of nebivolol hydrochloride | |
| CN102803256B (en) | Method for preparing (r)-3-(3-fluoro-4-(1-methyl-5,6-dihydro-1,2,4-triazin-4(1h)-yl)phenyl)-5-(substituted methyl)oxazolidin-2-one derivatives | |
| CA2660272A1 (en) | Process for making lactam tachykinin receptor antagonists | |
| JP2012254991A (en) | Method of producing tetra-substituted-5-azaspiro [2.4] heptane derivative, and optically active intermediate thereof | |
| CN112824381B (en) | Preparation method of piperidine amine | |
| JP4181233B2 (en) | Method for producing pyrrolidine-2,4-dione derivative | |
| US5235063A (en) | Process of preparing by condensation certain | |
| CN102321042B (en) | Preparation method of 3-substituted phenyl-5-hydroxymethyloxazolidine-2-ketone | |
| CN115894503A (en) | Preparation method of azacyclopentane derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |